He was first assigned to the support crew for the Apollo Soyuz Test Project. As such he was on the support crew for the Soyuz 16 flight which tested the new version of the Soyuz spacecraft that was to be used on the actual ASTP flight. He was then on the backup crew for Soyuz 19.

He then moved into the Salyut program. He was on the backup crew for Soyuz 25. This was meant to be the first mission to dock with Salyut 5. However it was unable to achieve a hard dock due to a faulty mechanism on the Soyuz. As such the craft was only in orbit for two days.

His first flight was Soyuz 26 which docked with Salyut 6. Launched December 10, 1977, it lasted until January 16, 1978, when Georgi Grechko and Romanenko landed in the Soyuz 27 spacecraft. The crew broke the space endurance record of 84 days that had been set by the Skylab 4 crew. They also performed the first EVA by a Russian crew in 9 years when they went 'outside' to check whether the docking apparatus had been damaged by the aborted Soyuz 25 mission. It was the first time that the Soviets had admitted that Salyut 6 had two docking ports.

The two docking ports allowed the Russians to launch a Progress freighter to the station. This contained supplies that would keep the station in orbit for longer than if it had to rely on what was launched with it. The Progress also transferred fuel to the station, the first time an in-orbit refuelling had occurred.

He was on the backup crew for Soyuz 33, an Intercosmos mission. Carrying the first Bulgarian cosmonaut it was meant to dock with Salyut 6 was a main engine malfunction error occurred forcing the docking to be aborted and a mission of only 2 days.

On September 18, 1980, Soyuz 38 launched carrying Romanenko and Arnaldo Tamayo-Mendez the first Cuban cosmonaut. They docked with Salyut 6 for a week long stay. By this time the station had been in orbit for over 1000 days and no longer had to new car smell that some of the first occupants said that it had. Some 20 joint experiments were conducted during the visit, including the growth of the first organic monocrystals in space using Cuban sugar.

Romanenko last flight was Soyuz TM-2 with Aleksandr Laveykin. This was the second expedition to Mir. During the flight he and Laveykin performed three EVAs. The first was unscheduled after Kvant-1 was unable to dock successfully with the Mir Core. They found a small rubbish bag was still in the docking port. The second installed the third solar array on the station and the third EVA finished the installation.

Laveykin developed a heart irregularities which meant that he returned to Earth with the visiting crew of Soyuz TM-3. He as replaced by Alexandr Alexandrov. The only other visitors to the station during Romanenko's stay was the crew of Soyuz TM-4, carrying Mir Expedition 3. Romanenko, Alexandrov and Anatoli Levchenko (who had launched with Soyuz TM-4) returned home in the Soyuz TM-4 capsule.

Romanenko's flight had lasted from February 5, 1987 until December 29, 1987. This stay of 326 days, 11 hours and 38 minutes was the longest at that time and the third longest of all time. The record was in fact broken by the Soyuz TM-4 crew.

In all he spent 430 days, 18 hours and 21 minutes in space over three missions. This is the tenth most accumalated time. He also has a total EVA time of 10 hours and 17 minutes over four EVAs.